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Abstract

A high proportion of young methamphetamine (MA) users simultaneously consume alcohol. However, the potential neurological and behavioural alterations induced by such a drug combination have not been systematically examined. Here, we studied in adolescent rats the long-term effects of alcohol, MA, and an alcohol-MA combination on anxiety-like behaviour, memory, and neurogenesis in the adult hippocampus. Rats received saline (control), ethanol (ETOH, 1.5 g/kg), MA (MA, 2 mg/kg), or ethanol and MA combined (ETHOH-MA, 1.5 g/kg ethanol plus 2 mg/kg MA) via oral gavage, once daily for 5 consecutive days. Open field (OF), elevated plus maze (EPM) and radial arm maze (RAM) tests were conducted following a 15-day withdrawal period. The results showed alterations in exploratory behaviour in the OF in the MA and ETOH-MA groups, and anxiety-like effects in the EPM in all three drug treatment groups. Further, all three drug groups exhibited reference memory deficits in the RAM, but only the combination treatment group displayed alterations in working memory performance. Neurogenesis was assessed by measuring the number of doublecortin(DCX)-void gaps, the length of such gaps and the pattern of arborisation of DCX+ neurons in the dentate gyrus (DG). Both MA and ETOH-MA treatments increased the length of DCX-void gaps in the DG but only ETOH-MA treatment increased the number of such gaps. An increased occurrence and length of the DCX-void gaps correlated with decreased exploratory activity in the OF, and impaired working memory in the RAM was associated with an augmented number of gaps. These findings suggest that persistent behavioural deficits are linked to the alterations in adult hippocampal neurogenesis produced by alcohol and MA exposure, and highlight the potential mental health risks associated with the simultaneous use of both substances.